A5076651825- Cancer, Hypoxia, and Metabolism
- Ubiquitin and proteasome pathways
- Microtubule and mitosis dynamics
- Mitochondrial Function and Pathology
- Protein Kinase Regulation and GTPase Signaling
- Acute Myeloid Leukemia Research
- ATP Synthase and ATPases Research
- Cancer-related Molecular Pathways
- Protein Degradation and Inhibitors
- Retinoids in leukemia and cellular processes
- Epigenetics and DNA Methylation
- Hedgehog Signaling Pathway Studies
- PI3K/AKT/mTOR signaling in cancer
- Cytokine Signaling Pathways and Interactions
- Cellular transport and secretion
- Cell Adhesion Molecules Research
- CAR-T cell therapy research
- Immune Cell Function and Interaction
- Chronic Myeloid Leukemia Treatments
- Computational Drug Discovery Methods
- interferon and immune responses
- Cellular Mechanics and Interactions
- CRISPR and Genetic Engineering
- Melanoma and MAPK Pathways
- Genetic and Kidney Cyst Diseases
Enzo Life Sciences (United States)
2019-2024
University of California, San Francisco
2013-2021
UCSF Helen Diller Family Comprehensive Cancer Center
2013-2021
Pediatrics and Genetics
2020
University of Alabama
2015
Howard Hughes Medical Institute
2013
Center for Cancer Research
2013
Universidad Católica de Santa Fe
2013
University of Chicago
2013
St. Jude Children's Research Hospital
2013
Inappropriate activation of the Hedgehog (Hh) signaling pathway has been implicated in a diverse spectrum cancers, and its pharmacological blockade emerged as an anti-tumor strategy. While nearly all known Hh antagonists target transmembrane protein Smoothened (Smo), small molecules that suppress downstream effectors could more comprehensively remediate pathway-dependent tumors. We report here four are epistatic to nucleocytoplasmic regulator Suppressor Fused [Su(fu)], including two can...
Only a subset of cancer patients respond to T-cell checkpoint inhibitors, highlighting the need for alternative immunotherapeutics. We performed CRISPR-Cas9 screens in leukemia cell line identify perturbations that enhance natural killer effector functions. Our defined critical components tumor-immune synapse and highlighted importance interferon-γ signaling modulating NK activity. Surprisingly, disrupting ubiquitin ligase substrate adaptor DCAF15 strongly sensitized cells NK-mediated...
The mitogen-activated protein kinase (MAPK) pathway is a critical effector of oncogenic RAS signaling, and MAPK inhibition may be an effective combination treatment strategy. We performed genome-scale loss-of-function CRISPR-Cas9 screens in the presence MEK1/2 inhibitor (MEKi) KRAS-mutant pancreatic lung cancer cell lines identified genes that cooperate with MEK inhibition. While we observed heterogeneity genetic modifiers MEKi sensitivity across lines, several recurrent classes synthetic...
Compounds that inhibit glutathione peroxidase 4 (GPX4) hold promise as cancer therapeutics in their ability to induce a form of nonapoptotic cell death called ferroptosis. Our research identified 24, structural analog the potent GPX4 inhibitor RSL3, has much better plasma stability (t1/2 > 5 h mouse plasma). The bioavailability 24 provided efficacious drug concentrations with IP dosing, thus enabling vivo studies assess tolerability and efficacy. An efficacy study using GPX4-sensitive tumor...
Engagement of integrin receptors with the extracellular matrix induces formation focal adhesions (FAs). Dynamic regulation FAs is necessary for cells to polarize and migrate. Key interactions between FA scaffolding signaling proteins are dependent on tyrosine phosphorylation. However, precise role phosphorylation in development maturation poorly defined. Here, we show that type Iγ phosphatidylinositol phosphate kinase (PIPKIγ661) 644 (Y644) critical its interaction talin, consequently,...
Membrane ruffle formation requires remodeling of cortical actin filaments, a process dependent upon the small G-protein Rac. Growth factors stimulate and membrane ruffling by integration signaling pathways that regulate actin-binding proteins. Phosphatidylinositol 4,5-bisphosphate (PIP2) regulates activity many proteins is produced type I phosphatidylinositol phosphate kinases (PIPKIs). Here we show in MG-63 cells only PIPKIalpha isoform localized to platelet-derived growth factor...
Clathrin-coated vesicles mediate sorting and intracellular transport of membrane-bound proteins. The formation these coats is initiated by the assembly adaptor proteins (AP), which specifically bind to membrane cargo via recognition endocytic motifs. lipid signaling molecule phosphatidylinositol 4,5-bisphosphate (PI(4,5)P<sub>2</sub>) critical for this process, as it serves both a targeting regulatory factor. PI(4,5)P<sub>2</sub> synthesized type I phosphate kinases (PIPKI). We have...
Biochemical properties of Ras oncoproteins and their transforming ability strongly support a dominant mechanism action in tumorigenesis. However, genetic studies unexpectedly suggested that wild-type (WT) exerts tumor suppressor activity. Expressing oncogenic Nras(G12D) the hematopoietic compartment mice induces an aggressive myeloproliferative neoplasm is exacerbated homozygous mutant animals. Here, we show increased gene dosage, but not inactivation WT Nras, underlies vivo behavior...
Significance The Hedgehog (Hh)/Gli signaling pathway is a key regulator of embryonic patterning and tissue homeostasis, its inappropriate activation can lead to several human cancers, including basal cell carcinoma, medulloblastoma, meningioma. To better understand the mechanisms that control Hh state, we have conducted genome-scale cDNA overexpression screen for proteins promote Gli-dependent transcription. Our studies reveal Arhgap36 be potent Gli activator, yielding first functional...
Oncogenic mutations in RAS provide a compelling yet intractable therapeutic target. Using co-immunoprecipitation mass spectrometry, we uncovered an interaction between and Argonaute 2 (AGO2). Endogenously, AGO2 co-sediment co-localize the endoplasmic reticulum. The N-terminal domain directly binds Switch II region of KRAS, agnostic nucleotide (GDP/GTP) binding. Functionally, knockdown attenuates cell proliferation mutant KRAS-dependent cells overexpression enhances KRASG12V-mediated...
Eradicating hedgehogs: The title molecule has been previously identified as a potent inhibitor of the Hedgehog signaling pathway, which gives embryonic cells information needed to develop properly. This is shown modulate target gene expression by depolymerizing microtubules, thus revealing dual roles cytoskeleton in pathway regulation (see figure).
Type I IFN signaling is a crucial component of antiviral immunity that has been linked to promoting the efficacy some chemotherapeutic drugs. We developed reporter system in HCT116 cells detects activation endogenous IFI27 locus, an target gene. screened library annotated compounds these and discovered Aurora kinase inhibitors (AURKi) as strong hits. was found be most enriched gene signature after AURKi treatment HCT116, this also strongly other colorectal cancer cell lines. The ability...
Abstract Oncogenic KRAS mutations introduce discrete amino acid substitutions that reduce intrinsic Ras GTPase activity and confer resistance to GTPase-activating proteins (GAPs). Here we discover a partial duplication of the switch 2 domain K-Ras encoding tandem repeat acids G60_A66dup in child with an atypical myeloproliferative neoplasm. containing this or similar five E62_A66dup mutation identified lung colon cancers transform growth primary myeloid progenitors Ba/F3 cells. Recombinant...
Imprinted genes are expressed from only one parental allele and heterozygous loss involving the is sufficient to produce complete of protein expression. Genetic alterations common in tumorigenesis but role imprinted this process not well understood. In earlier work we mutagenized mice for Neurofibromatosis I tumor suppressor gene (NF1) model radiotherapy-associated second malignant neoplasms that arise irradiated NF1 patients. Expression analysis cell lines established our mouse models...
Abstract The Werner syndrome helicase (WRN) has emerged as a promising synthetic lethal target in cancers with microsatellite instability (MSI). This discovery spurred numerous efforts developing therapeutics targeting WRN and the advancement of at least two programs into Phase I clinical trials. development acquired resistance remains significant obstacle for durable efficacy targeted therapies oncology this challenge may be particularly pronounced setting mismatch repair deficient (dMMR)...